Latest publication:
Kotecha M. et al. (2008). Inhibition of DNA binding of the NF-Y transcription factor by the pyrrolobenzodiazepine-polyamide conjugate GWL-78. Mol Cancer Ther 7(5) 1319-1328.
This publication details impressive proof-of-concept for the small molecule transcription factor-binding inhibitor SG2274 (GWL-78), and provides a basis for novel anti-neoplastic gene-targeted therapies.
Many genes involved in cell cycle control are regulated by the transcription factor NF-Y. Blocking the interaction of NF-Y with DNA in selected genes has a potential therapeutic application in cancer. In this study, the ability of SG2274 (GWL-78), a pyrrolobenzodiazepine-polypyrrole conjugate, to inhibit the binding of NF-Y to DNA was investigated.
SG2274 was shown to displace NF-Y bound to specific DNA sequences within genes involved in cell cycle progression. SG2274 bound to AT-rich sequences corresponding to the preferred binding site of NF-Y in the Topoisomerase II-alpha promoter. SG2274 was also able to displace NF-Y from DNA, and ChIP assays on the topoisomerase II-alpha promoter showed that SG2274 was able to enter the nucleus and interact with specific DNA sequences. Treatment fibroblast cells with SG2274 blocked the cell cycle. SG2274 may be useful in modulating transcription and blocking cellular proliferation.
Download: Kotecha et al 2008